Giovannetti E, Leon L G, Bertini S, Macchia M, Minutolo F, Funel N, Alecci C, Giancola F, Danesi R, Peters G J
Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
Nucleosides Nucleotides Nucleic Acids. 2010 Jun;29(4-6):419-26. doi: 10.1080/15257771003730193.
This study investigated the interaction between the novel ceramide analog AL6 and gemcitabine in MIA PaCa-2 and PANC-1 pancreatic cancer cell lines, harboring different polymorphic variants of the gemcitabine catabolism enzyme cytidine deaminase (CDA). AL6 dose-dependently inhibited cell growth, induced apoptosis and synergistically enhanced the cytotoxic activity of gemcitabine. Moreover, it triggered apoptosis, which was significantly enhanced by the combination, and increased the ratio between gene expression of the activating enzyme deoxycytidine kinase (dCK) and CDA, potentially favoring gemcitabine activity. In conclusion, AL6 displays synergistic cytotoxic activity, enhances apoptosis, and favorably modulates enzymes involved in gemcitabine metabolism, supporting future investigation of this combination in pancreatic cancer.
本研究调查了新型神经酰胺类似物AL6与吉西他滨在MIA PaCa-2和PANC-1胰腺癌细胞系中的相互作用，这两种细胞系携带吉西他滨分解代谢酶胞苷脱氨酶（CDA）的不同多态性变体。AL6呈剂量依赖性抑制细胞生长、诱导凋亡并协同增强吉西他滨的细胞毒活性。此外，它引发凋亡，联合用药时凋亡显著增强，并且增加了激活酶脱氧胞苷激酶（dCK）与CDA的基因表达比值，这可能有利于吉西他滨发挥活性。总之，AL6具有协同细胞毒活性，增强凋亡，并有利地调节参与吉西他滨代谢的酶，支持未来对该联合用药在胰腺癌中的研究。
